Papillomaviruses (PV) are small double stranded DNA non-enveloped viruses that infect a wide range of organisms causing benign epithelial and fibroepithelial lesions (warts). HPVs have been implicated as the etiologic agent for several malignancies including cervical and anal carcinoma. The number of cervical cancer cases is estimated to be up to 1.4 million worldwide by the World Health Organization. There are approximately 500,000 cases diagnosed worldwide each year and half of these women will die. Additionally, women with acquired immune deficiency (AIDS) have rates of invasive cervical carcinoma 13 to 18 times higher as compared to the general population. HIV infected men with a history of anal intercourse have rates of anal cancer equivalent to those of cervical carcinoma before the advent of the Pap-smear screening. In the United States, over 50 million Pap tests are performed that identify approximately 14,000 cases of cervical cancer. Reducing the number of papillomavirus infections worldwide would have a tremendous impact on the number of cervical cancers cases. Therefore understanding the infectious pathway of papillomaviruses raises the possibility of developing prophylactic vaccines. A goal of this work is to study viral entry and provide therapeutic targets to prevent PV infections. PV virions consist of two structural viral proteins, L1 and L2 at a ratio of approximately 30 L1s to 1 L2. Antibodies directed at L2 have been shown to be neutralizing, suggesting the role of L2 in viral entry and/or attachment. Our goal is to determine the role of L2 in viral infection. We hypothesize that L2 mediates infection by directing the intracellular movement of the viral particles to the endoplasmic reticulum. We have identified the physical interaction of L2 protein with the endoplasmic reticulum (ER) resident protein syntaxin 18. Our data show that disrupting the ability of L2 protein to interact and co-localize with syntaxin 18 results in loss of viral infectivity. We also identified the residues in L2 responsible for this trafficking. We propose to identify the route of entry used by the virions to reach the ER, and address if virus disassembly and genome release are occurring in the ER. [unreadable] [unreadable]